Project Summary It has been clearly demonstrated that exposure to the environmental toxicant cadmium is associated with a variety of human diseases including prostate cancer. Prostate cancer is the second leading cause of cancer death in United States. Although an association has been established, the mechanism by which this metal induces cellular transformation has yet to be defined. One underexplored process that may be affected by cadmium is oncogenic autophagy, a process that promotes cancer cell survival. Our preliminary data clearly shows that chronic exposure to cadmium leads to cellular transformation and that this transformation occurs via autophagy through changes in Placenta Specific 8 (Plac8) expression. Additionally, Plac8 is observed in human prostate cancer, but not in benign prostatic hyperplasia tissues. Based on our preliminary results we hypothesize that cadmium-induced cellular transformation is mediated by the induction of autophagy and that Plac8 is an essential regulator of this process. We will test this hypothesis using a combination of approaches in normal prostate epithelial (RWPE-1), transforming cells and cadmium-transformed prostate epithelial (CTPE) cells, mice and human prostate cancer. The goals of this project are to explore an innovative model for the regulation of autophagy by cadmium; where short term metal exposure induces the apoptosis, while chronic low dose exposure, which more accurately represents human etiology of cadmium toxicity; autophagy acts oncogenic leading to transformation. The interaction between cadmium, autophagy/apoptosis and Plac8 expression will be defined using three approaches: Specific Aim 1: Establish the mechanistic relationship between cadmium exposure and the induction of autophagy in prostate epithelial cells. Specific Aim 2: Determine the mechanism by-which cadmium induces Plac8 expression to regulate pro-survival signaling autophagy. Specific Aim -3: Determine the oncogenic role of Plac8 in vivo. The successful completion of these goals represents the first studies on the role of autophagy/Plac8 in cadmium- induced prostate cancer. It will also inform on the applicability of using Plac8 as a prostate cancer biomarker and of targeting this protein to inhibit metal-induced prostate cancer.